Substituted pyrazolo[1,5-a] pyrimidines as protein kinase inhibitors

ABSTRACT

In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of protein and/or checkpoint kinases, methods of preparing such compounds, pharmaceutical compositions including one or more such compounds, methods of preparing pharmaceutical formulations including one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the protein or checkpoint kinases using such compounds or pharmaceutical compositions. An illustrative compound is shown below:

FIELD OF THE INVENTION

The present invention relates to substituted pyrazolo[1,5-a]pyrimidinecompounds useful as protein kinase inhibitors, regulators or modulators,pharmaceutical compositions containing the compounds, and methods oftreatment using the compounds and compositions to treat diseases suchas, for example, cancer, inflammation, arthritis, viral diseases,neurodegenerative diseases such as Alzheimer's disease, cardiovasculardiseases, and fungal diseases. This application claims priority fromU.S. provisional patent application Ser. No. 60/724,159 filed Oct. 6,2005.

BACKGROUND OF THE INVENTION

Protein kinases are a family of enzymes that catalyze phosphorylation ofproteins, in particular the hydroxyl group of specific tyrosine, serine,or threonine residues in proteins. Protein kinases are pivotal in theregulation of a wide variety of cellular processes, includingmetabolism, cell proliferation, cell differentiation, and cell survival.Uncontrolled proliferation is a hallmark of cancer cells, and can bemanifested by a deregulation of the cell division cycle in one of twoways—making stimulatory genes hyperactive or inhibitory genes inactive.Protein kinase inhibitors, regulators or modulators alter the functionof kinases such as cyclin-dependent kinases (CDKs), mitogen activatedprotein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Chkkinases, AKT kinases and the like. Examples of protein kinase inhibitorsare described in WO02/22610 A1 and by Y. Mettey et al in J. Med. Chem.,(2003) 46 222-236.

The cyclin-dependent kinases are serine/threonine protein kinases, whichare the driving force behind the cell cycle and cell proliferation.Misregulation of CDK function occurs with high frequency in manyimportant solid tumors. Individual CDK's, such as, CDK1, CDK2, CDK3,CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct roles incell cycle progression and can be classified as either G1, S, or G2Mphase enzymes. CDK2 and CDK4 are of particular interest because theiractivities are frequently misregulated in a wide variety of humancancers. CDK2 activity is required for progression through G1 to the Sphase of the cell cycle, and CDK2 is one of the key components of the G1checkpoint. Checkpoints serve to maintain the proper sequence of cellcycle events and allow the cell to respond to insults or toproliferative signals, while the loss of proper checkpoint control incancer cells contributes to tumorgenesis. The CDK2 pathway influencestumorgenesis at the level of tumor suppressor function (e.g. p52, RB,and p27) and oncogene activation (cyclin E). Many reports havedemonstrated that both the coactivator, cyclin E, and the inhibitor,p27, of CDK2 are either over- or underexpressed, respectively, inbreast, colon, nonsmall cell lung, gastric, prostate, bladder,non-Hodgkin's lymphoma, ovarian, and other cancers. Their alteredexpression has been shown to correlate with increased CDK2 activitylevels and poor overall survival. This observation makes CDK2 and itsregulatory pathways compelling targets for the development of cancertreatments.

A number of adenosine 5′-triphosphate (ATP) competitive small organicmolecules as well as peptides have been reported in the literature asCDK inhibitors for the potential treatment of cancers. U.S. Pat. No.6,413,974, col. 1, line 23-col. 15, line 10 offers a good description ofthe various CDKs and their relationship to various types of cancer.Flavopiridol (shown below) is a nonselective CDK inhibitor that iscurrently undergoing human clinical trials, A. M. Sanderowicz et al, J.Clin. Oncol. (1998) 16, 2986-2999.

Other known inhibitors of CDKs include, for example, olomoucine (J.Vesely et al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I.Meijer et al, Eur. J. Biochem., (1997) 243, 527-536). U.S. Pat. No.6,107,305 describes certain pyrazolo[3,4-b]pyridine compounds as CDKinhibitors. An illustrative compound from the '305 patent is:

K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162disclose certain aminothiazole compounds as CDK inhibitors.

Pyrazolopyrimidines are known. For example, WO92/18504, WO02/50079,WO95/35298, WO02/40485, EP94304104.6, EP0628559 (equivalent to U.S. Pat.Nos. 5,602,136, 5,602,137 and 5,571,813), U.S. Pat. No. 6,383,790, Chem.Pharm. Bull., (1999) 47 928, J. Med. Chem., (1977) 20, 296, J. Med.Chem., (1976) 19 517 and Chem. Pharm. Bull., (1962) 10 620 disclosevarious pyrazolopyrimidines. Other publications of interest include:U.S. Pat. Nos. 5,688,949 and 6,313,124, WO 98/54093, WO 03/101993, WO03/091256, WO 04/089416 and DE 10223917.

Another series of protein kinases are those that play an important roleas a checkpoint in cell cycle progression. Checkpoints prevent cellcycle progression at inappropriate times, such as in response to DNAdamage, and maintain the metabolic balance of cells while the cell isarrested, and in some instances can induce apoptosis (programmed celldeath) when the requirements of the checkpoint have not been met.Checkpoint control can occur in the G1 phase (prior to DNA synthesis)and in G2, prior to entry into mitosis.

One series of checkpoints monitors the integrity of the genome and, uponsensing DNA damage, these “DNA damage checkpoints” block cell cycleprogression in G.sub.1 & G.sub.2 phases, and slow progression through Sphase. This action enables DNA repair processes to complete their tasksbefore replication of the genome and subsequent separation of thisgenetic material into new daughter cells takes place. Inactivation ofCHK1 has been shown to transduce signals from the DNA-damage sensorycomplex to inhibit activation of the cyclin B/Cdc2 kinase, whichpromotes mitotic entry, and abrogate G.sub.2 arrest induced by DNAdamage inflicted by either anticancer agents or endogenous DNA damage,as well as result in preferential killing of the resulting checkpointdefective cells. See, e.g., Peng et al., Science, 277, 1501-1505 (1997);Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91, 865-867(1997); Weinert, Science, 277, 1450-1451 (1997); Walworth et al.,Nature, 363, 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell.,5, 147-160 (1994).

Selective manipulation of checkpoint control in cancer cells couldafford broad utilization in cancer chemotherapeutic and radiotherapyregimens and may, in addition, offer a common hallmark of human cancer“genomic instability” to be exploited as the selective basis for thedestruction of cancer cells. A number of factors place CHK1 as a pivotaltarget in DNA-damage checkpoint control. The elucidation of inhibitorsof this and functionally related kinases such as CDS1/CHK2, a kinaserecently discovered to cooperate with CHK1 in regulating S phaseprogression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka,Science, 282, 1893-1897 (1998)), could provide valuable new therapeuticentities for the treatment of cancer.

Another group of kinases are the tyrosine kinases. Tyrosine kinases canbe of the receptor type (having extracellular, transmembrane andintracellular domains) or the non-receptor type (being whollyintracellular). Receptor-type tyrosine kinases are comprised of a largenumber of transmembrane receptors with diverse biological activity. Infact, about 20 different subfamilies of receptor-type tyrosine kinaseshave been identified. One tyrosine kinase subfamily, designated the HERsubfamily, is comprised of EGFR (HER1), HER2, HER3 and HER4. Ligands ofthis subfamily of receptors identified so far include epithelial growthfactor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.Another subfamily of these receptor-type tyrosine kinases is the insulinsubfamily, which includes INS-R, IGF-IR, IR, and IR-R. The PDGFsubfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit andFLK-II. The FLK family is comprised of the kinase insert domain receptor(KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase4 (FLK4) and thefms-like tyrosine kinase-1 (flt-1). For detailed discussion of thereceptor-type tyrosine kinases, see Plowman et al., DN&P 7(6): 334-339,1994.

At least one of the non-receptor protein tyrosine kinases, namely, LCK,is believed to mediate the transduction in T-cells of a signal from theinteraction of a cell-surface protein (Cd4) with a cross-linked anti-Cd4antibody. A more detailed discussion of non-receptor tyrosine kinases isprovided in Bolen, Oncogene, 8, 2025-2031 (1993). The non-receptor typeof tyrosine kinases is also comprised of numerous subfamilies, includingSrc, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Eachof these subfamilies is further sub-divided into varying receptors. Forexample, the Src subfamily is one of the largest and includes Src, Yes,Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes hasbeen linked to oncogenesis. For a more detailed discussion of thenon-receptor type of tyrosine kinases, see Bolen, Oncogene, 8:2025-2031(1993).

In addition to its role in cell-cycle control, protein kinases also playa crucial role in angiogenesis, which is the mechanism by which newcapillaries are formed from existing vessels. When required, thevascular system has the potential to generate new capillary networks inorder to maintain the proper functioning of tissues and organs. In theadult, however, angiogenesis is fairly limited, occurring only in theprocess of wound healing and neovascularization of the endometriumduring menstruation. On the other hand, unwanted angiogenesis is ahallmark of several diseases, such as retinopathies, psoriasis,rheumatoid arthritis, age-related macular degeneration, and cancer(solid tumors). Protein kinases which have been shown to be involved inthe angiogenic process include three members of the growth factorreceptor tyrosine kinase family; VEGF-R2 (vascular endothelial growthfactor receptor 2, also known as KDR (kinase insert domain receptor) andas FLK 1); FGF-R (fibroblast growth factor receptor); and TEK (alsoknown as Tie-2).

VEGF-R2, which is expressed only on endothelial cells, binds the potentangiogenic growth factor VEGF and mediates the subsequent signaltransduction through activation of its intracellular kinase activity.Thus, it is expected that direct inhibition of the kinase activity ofVEGF-R2 will result in the reduction of angiogenesis even in thepresence of exogenous VEGF (see Strawn et al, Cancer Research, 56,3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which failto mediate signal transduction. Millauer et al, Cancer Research, 56,1615-1620 (1996). Furthermore, VEGF-R2 appears to have no function inthe adult beyond that of mediating the angiogenic activity of VEGF.Therefore, a selective inhibitor of the kinase activity of VEGF-R2 wouldbe expected to exhibit little toxicity.

Similarly, FGFR binds the angiogenic growth factors aFGF and bFGF andmediates subsequent intracellular signal transduction. Recently, it hasbeen suggested that growth factors such as bFGF may play a critical rolein inducing angiogenesis in solid tumors that have reached a certainsize. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). UnlikeVEGF-R2, however, FGF-R is expressed in a number of different cell typesthroughout the body and may or may not play important roles in othernormal physiological processes in the adult. Nonetheless, systemicadministration of a small molecule inhibitor of the kinase activity ofFGF-R has been reported to block bFGF-induced angiogenesis in micewithout apparent toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904(1998).

TEK (also known as Tie-2) is another receptor tyrosine kinase expressedonly on endothelial cells which has been shown to play a role inangiogenesis. The binding of the factor angiopoietin-1 results inautophosphorylation of the kinase domain of TEK and results in a signaltransduction process which appears to mediate the interaction ofendothelial cells with peri-endothelial support cells, therebyfacilitating the maturation of newly formed blood vessels. The factorangiopoietin-2, on the other hand, appears to antagonize the action ofangiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al.,Science, 277, 55-60 (1997).

Pim-1 is a small serine/threonine kinase. Elevated expression levels ofPim-1 have been detected in lymphoid and myeloid malignancies, andrecently Pim-1 was identified as a prognostic marker in prostate cancer.K. Peltola, “Signaling in Cancer: Pim-1 Kinase and its Partners”,Annales Universitatis Turkuensis, Sarja-Ser. D Osa-Tom. 616, (Aug. 30,2005), http://kirjasto.utu.fi/julkaisupalvelut/annaalit/2004/D616.html.Pim-1 acts as a cell survival factor and may prevent apoptosis inmalignant cells. K. Petersen Shay et al., Molecular Cancer Research3:170-181 (2005).

There is a need for effective inhibitors of protein kinases in order totreat or prevent disease states associated with abnormal cellproliferation. Moreover, it is desirable for kinase inhibitors topossess both high affinity for the target kinase as well as highselectivity versus other protein kinases. Small-molecule compounds thatmay be readily synthesized and are potent inhibitors of cellproliferation are those, for example, that are inhibitors of one or moreprotein kinases, such as CHK1, CHK2, VEGF, CDKs or CDK/cyclin complexesand both receptor and non-receptor tyrosine kinases.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides substitutedpyrazolo[1,5-a]pyrimidine compounds, methods of preparing suchcompounds, pharmaceutical compositions comprising one or more suchcompounds, methods of preparing pharmaceutical formulations comprisingone or more such compounds, and methods of treatment, prevention,inhibition or amelioration of one or more diseases associated with theprotein kinases using such compounds or pharmaceutical compositions.

In one aspect, the present invention provides compounds represented bythe structural formula (I):

or a pharmaceutically acceptable salt, solvate, ester, or prodrug of thecompound of Formula (I), wherein:

R² is selected from the group consisting of H, alkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, alkenylalkyl,alkynylalkyl, heterocyclyl, heterocycloalkyl, trifluoromethyl, halo,—CN, —OCF₃, —CO₂R⁸, —CONR⁸R⁹, —OR^(8a), —SR⁸, —SO₂R⁸, —SO₂NR⁸R⁹,—NR⁸SO₂R⁹, —NR⁸COR⁹, and —NR⁸CONR⁸R⁹;

R³ is selected from the group consisting of haloalkyl, alkenyl, alkynyl,aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl,alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —NR⁵R^(8a), —NR⁸COR⁹, —NR⁸SO₂R⁹, —COR⁸, —CO₂R⁸,—CONR⁸R⁹, —CH₂OR⁸, —OR^(8b), —SR⁸, —SO₂R⁸, —S(O₂)NR⁸R⁹, —S(O₂)aryl,—S(O₂)heteroaryl, —C(O)NR⁸R⁹, —C(O)OR⁹, —C(O)aryl, —C(O)heteroaryl,—(CHR⁵)_(n)-aryl, —(CHR⁵)_(n)-heteroaryl,

wherein each of the alkyl, alkenyl, alkynyl, aryl, arylalkyl,arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and theheterocyclic moieties shown immediately above for R³ can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of H, halo, alkyl, trifluoromethyl, —OR⁸,—NR⁸R⁹, —SR⁸, —SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and —NO₂.;

R⁴ is selected from the group consisting of H, halo, haloalkyl, alkyl,alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —NR⁸R⁹, —NR⁸COR⁹,—NR⁸SO₂R⁹, —COR⁸, —CO₂R⁸, —CONR⁸R⁹, —CH₂OR⁸, —OR⁸, —SR⁸, —SO₂R⁸,—S(O₂)NR⁸R⁹, —S(O₂)aryl, —S(O₂)heteroaryl, —C(O)OR⁹, —C(O)aryl,—C(O)heteroaryl, —(CHR⁵)_(n)-aryl, —(CHR⁵)_(n)-heteroaryl,

wherein each of the alkyl, alkenyl, alkynyl, aryl, arylalkyl,arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and theheterocyclic moieties shown immediately above for R⁴ can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of H, halo, alkyl, trifluoromethyl, —OR⁸,—NR⁸R⁹, —SR⁸, —SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and —NO₂;

R^(a) is selected from the group consisting of H, halo, haloalkyl,alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —NR⁸R⁹, —NR⁸COR⁹,—NR⁸SO₂R⁹, —COR⁸, —CO₂R⁸, —CONR⁸R⁹, —CH₂R⁸, —OR⁸, —SR⁸, —SO₂R⁸,—S(O₂)NR⁸R⁹, —S(O₂)aryl, —S(O₂)heteroaryl, —C(O)OR⁹, —C(O)aryl,—C(O)heteroaryl, —(CHR⁵)_(n)-aryl, —(CHR⁵)_(n)-heteroaryl,

wherein each of the alkyl, alkenyl, alkynyl, aryl, arylalkyl,arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and theheterocyclic moieties shown immediately above for R^(a) can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of H, halo, alkyl, trifluoromethyl, —OR⁸,—NR⁸R⁹, —SR⁸, —SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and —NO₂;

R⁵ is selected from the group consisting of H, alkyl, aryl orcycloalkyl;

R⁶ is selected from the group consisting of H, alkyl, alkenyl, aryl,arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl,aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl groups can be unsubstituted oroptionally substituted with one or more moieties which can be the sameor different, each moiety being independently selected from the groupconsisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF₃,—OCF₃, —CN, —OR⁵, —NR⁵R¹⁰, —C(R⁵R¹¹)_(p)—R⁹, —N(R⁵)Boc,—(CR⁵R¹¹)_(p)OR⁵, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰,—S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰;

R⁷ is selected from the group consisting of alkyl, cycloalkyl, aryl,arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl,and heterocyclyl, wherein each of the alkyl, cycloalkyl,heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl,heteroarylalkyl, heteroarylalkenyl, and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —CH₂OR⁵, —C(O₂)R⁵,—C(O)NR⁵R¹⁰, —C(O)R⁵, —SR¹⁰, —S(O₂)R¹⁰, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R¹⁰,—N(R⁵)C(O)R¹⁰ and —N(R⁵)C(O)NR⁵R¹⁰;

R⁸ is selected from the group consisting of H, —OR⁶, —NR⁵R⁶,—C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷, —C(═N—CN)—NH₂, —C(═NH)—NHR⁵,heterocyclyl, —S(O₂)R⁷,

—OR10, —CF₃, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl,wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groupscan be unsubstituted or optionally substituted with one or more moietieswhich can be the same or different, each moiety being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,heterocyclylalkyl, —CF₃, —OCF₃, —CN, —OR⁵, —NR⁵R¹⁰, —C(R⁵R¹¹)_(p)—R⁹,—N(R⁵)Boc, —(CR⁵R¹¹)_(p)OR⁵, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰, —SO₃H,—SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰;

R^(8a) is selected from the group consisting of —OR⁶, —NR⁵R⁶,—C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷, —C(═N—CN)—NH₂, —C(═NH)—NHR⁵,heterocyclyl, —S(O₂)R⁷,

—OR10, —CF₃, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl,wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groupscan be unsubstituted or optionally substituted with one or more moietieswhich can be the same or different, each moiety being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,heterocyclylalkyl, —CF₃, —OCF₃, —CN, —OR⁵, —NR⁵R¹⁰, —C(R⁵R¹¹)_(p)—R⁹,—N(R⁵)Boc, —(CR⁵R¹¹)_(p)OR⁵, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰, —SO₃H,—SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰;

R^(8b) is selected from the group consisting of —OR⁶, —NR⁵R⁶,—C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷, —C(═N—CN)—NH₂, —C(═NH)—NHR⁵,heterocyclyl, —S(O₂)R⁷,

—OR¹⁰, —CF₃, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl,wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groupscan be unsubstituted or optionally substituted with one or more moietieswhich can be the same or different, each moiety being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,heterocyclylalkyl, —CF₃, —OCF₃, —CN, —OR⁵, —NR⁵R¹⁰, —C(R⁵R¹¹)_(p)—R⁹,—N(R⁵)Boc, —(CR⁵R¹¹)_(p)OR⁵—C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰,—S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰;

R⁹ is selected from the group consisting of H, —OR⁶, —NR⁵R⁶,—C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷, —C(═N—CN)—NH₂, —C(═NH)—NHR⁵,heterocyclyl, —S(O₂)R⁷,

—OR10, —CF₃, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl,wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groupscan be unsubstituted or optionally substituted with one or more moietieswhich can be the same or different, each moiety being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,heterocyclylalkyl, —CF₃, —OCF₃, —CN, —OR⁵, —NR⁵R¹⁰, —C(R⁵R¹¹)_(p)—R⁹,—N(R⁵)Boc, —(CR⁵R¹¹)_(p)OR⁵—C(O₂)R⁵, —C(O)R⁵—C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰,—S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰;

R¹⁰ is selected from the group consisting of H, alkyl, alkenyl, aryl,arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl,aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl groups can be unsubstituted oroptionally substituted with one or more moieties which can be the sameor different, each moiety being independently selected from the groupconsisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF₃,—OCF₃, —CN, —OR⁵, —NR⁵R¹¹, —C(R⁵R¹¹)_(p)—R⁹, —N(R⁵)Boc,—(CR⁵R¹¹)_(p)OR⁵, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹¹, —SO₃H, —SR¹⁰,—S(O₂)R⁷, —S(O₂)NR⁵R¹¹, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹¹;

or optionally (i) R⁵ and R¹¹ in the moiety —NR⁵R¹¹, or (ii) R⁵ and R⁶ inthe moiety —NR⁵R⁶, may be joined together to form a cycloalkyl orheterocyclyl moiety, with each of the cycloalkyl or heterocyclyl moietybeing unsubstituted or optionally independently being substituted withone or more R⁹ groups; and

R¹¹ is H, halo or alkyl;

m is 0 to 4;

n is 1 to 4; and

p is 1 to 4,

with the following provisos:

-   -   (a) When R² is as defined above, then at least one of R³, R⁴ and        R^(a) is selected from the group consisting of —NH₂, —OH,        alkoxy, alkylthio, halo, alkynyl, alkenylalkyl, and        alkynylalkyl; or    -   (b) When R³, R⁴ and R^(a) are as defined above, then R² is        selected from the group consisting of alkyl, cycloalkyl,        cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, alkenylalkyl,        alkynylalkyl, trifluoromethyl, —OCF₃, —OR^(8a), —SR⁸, and        —NR⁸CONR⁸R⁹.

The compounds of Formula I can be useful as protein kinase inhibitorsand can be useful in the treatment and prevention of proliferativediseases, for example, cancer, inflammation and arthritis,neurodegenerative diseases such Alzheimer's disease, cardiovasculardiseases, viral diseases and fungal diseases.

DETAILED DESCRIPTION

The present invention provides substituted pyrazolo[1,5-a]pyrimidinecompounds which are represented by structural Formula I, orpharmaceutically acceptable salts, solvates, esters, or prodrugsthereof, wherein the various moieties are as described above.

Referring to Formula (I) above, in some embodiments, R² is H.

In other embodiments, R² is Br.

In other embodiments, R² is selected from the group consisting of Cl,—SH, —CN, alkyl, alkenyl, alkynyl, and cyclopropyl.

In other embodiments, R² is selected from the group consisting ofcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, —OCF₃,—CO₂R⁸, —CONR⁸R⁹, —OR^(8a), —SR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂R⁹,—NR⁸COR⁹, and —NR⁸CONR⁸R⁹.

In some embodiments, R³ is benzyl.

In other embodiments, R³ is methyl.

In other embodiments, R³ is selected from the group consisting of aryl,arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —S(O₂)aryl,—S(O₂)heteroaryl, —C(O)aryl, —C(O)heteroaryl,

—(CHR⁵)_(n)-aryl, —(CHR⁵)_(n)-heteroaryl,

wherein each of the aryl, arylalkyl, arylalkenyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl and the heterocyclic moieties shown immediately abovefor R³ can be unsubstituted or optionally substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from the group consisting of H, halo, alkyl,trifluoromethyl, —OR⁸, —NR⁸R⁹, —SR⁸, —SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and—NO_(2.)

In other embodiments, R³ is selected from the group consisting ofhaloalkyl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, —NR⁵R^(8a),—NR⁸COR⁹, —NR⁸SO₂R⁹, —COR⁸, —CO₂R⁸, —CONR⁸R⁹, —CH₂OR⁸, OR^(8b), —SR⁸,—SO₂R⁸, —S(O₂)NR⁸R⁹, wherein each of the alkyl, alkenyl, alkynyl,alkenylalkyl, alkynylalkyl, can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of H, halo, alkyl, trifluoromethyl, —OR⁸, —NR⁸R⁹, —SR⁸,—SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and —NO_(2.)

In other embodiments, R³ is alkoxy.

In other embodiments, R³ is alkylthio.

In other embodiments, R³ is selected from the group consisting of

In other embodiments, R³ is aryl substituted with 1-3 aryl or heteroarylgroups which can be the same or different and are each independentlyselected from the group consisting of phenyl, pyridyl, thiophenyl,furanyl and thiazolo groups.

In other embodiments, R³ is heteroaryl substituted with 1-3 aryl orheteroaryl groups which can be the same or different and are eachindependently selected from the group consisting of phenyl, pyridyl,thiophenyl, furanyl and thiazolo groups.

In other embodiments, R³ is selected from the group consisting ofheteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl.

In some embodiments, R³ is phenyl.

In some embodiments, R⁴ is H.

In other embodiments, R⁴ is selected from the group consisting of Cl,Br, —OH, —SH, alkyl, alkenyl, alkynyl, haloalkyl and cyclopropyl.

In other embodiments, R⁴ is —NH₂.

In other embodiments, R⁴ is —OH.

In other embodiments, R⁴ is alkoxy.

In other embodiments, R⁴ is alkylthio.

In other embodiments, R⁴ is halo.

In some embodiments, R^(a) is —NH₂.

In other embodiments, R^(a) is —OH.

In other embodiments, R^(a) is alkoxy.

In other embodiments, R^(a) is alkylthio.

In other embodiments, R^(a) is halo.

In other embodiments, R^(a) is Cl.

In some embodiments, R⁵ is H.

In some embodiments, n is 1.

In some embodiments, p is 1.

Non-limiting examples of compounds of Formula (I) include:

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limiting examples of suitablealkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.Non-limiting example of a suitable alkylaryl group is tolyl. The bond tothe parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietyare methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” mayalso mean a single moiety (e.g., carbonyl) which simultaneously replacestwo available hydrogens on the same carbon atom on a ring system.Example of such moiety is pyrrolidone:

“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”may also mean a single moiety (e.g., carbonyl) which simultaneouslyreplaces two available hydrogens on the same carbon atom on a ringsystem. Example of such moiety is pyrrolidinone:

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process or natural source or combinationthereof. Thus, the term “purified”, “in purified form” or “in isolatedand purified form” for a compound refers to the physical state of saidcompound after being obtained from a purification process or processesdescribed herein or well known to the skilled artisan, in sufficientpurity to be characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

Compounds of Formula I, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

The compounds according to the invention can have pharmacologicalproperties; in particular, the compounds of Formula (I) can beinhibitors, regulators or modulators of protein kinases. Non-limitingexamples of protein kinases that can be inhibited, regulated ormodulated include cyclin-dependent kinases (CDKs), such as, CDK1, CDK2,CDK3, CDK4, CDK5, CDK6, CDK7, and CDK8, mitogen activated protein kinase(MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Chk kinases, such asChk1 and Chk2, Pim-1 kinases, tyrosine kinases, such as the HERsubfamily (including, for example, EGFR (HER1), HER2, HER3 and HER4),the insulin subfamily (including, for example, INS-R, IGF-IR, IR, andIR-R), the PDGF subfamily (including, for example, PDGF-alpha and betareceptors, CSFIR, c-kit and FLK-II), the FLK family (including, forexample, kinase insert domain receptor (KDR), fetal liver kinase-1(FLK-1), fetal liver kinase4 (FLK4) and the fms-like tyrosine kinase-1(flt-1)), non-receptor protein tyrosine kinases, for example LCK, Src,Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK, growthfactor receptor tyrosine kinases such as VEGF-R2, FGF-R, TEK, Aktkinases and the like.

The compounds of Formula (I) can be inhibitors of protein kinases suchas, for example, the inhibitors of the checkpoint kinases such as Chk1,Chk2 and the like. Preferred compounds can exhibit IC₅₀ values of lessthan about 25 μm, preferably about 0.001 to about 1.0 μm, and morepreferably about 0.001 to about 0.1 μm. The assay methods are describedin the Examples set forth below.

The compounds of Formula (I) can be inhibitors of protein kinases suchas, for example, the cyclin-dependent kinases such as CDK1, CDK2, CDK3,CDK4, CDK5, CDK6, CDK7, and CDK8, and the like. The compounds shown inTable 1 exhibited CDK2 inhibitory activity (IC₅₀) of about 0.0001 μMto >about 5 μM. The assay methods are described in the examples below.

TABLE 1 Structure CDK2 IC₅₀ (μM)

0.08

4.67

The compounds of Formula (I) can be useful in the therapy ofproliferative diseases such as cancer, autoimmune diseases, viraldiseases, fungal diseases, neurological/neurodegenerative disorders,arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy),neuronal, alopecia and cardiovascular disease. Many of these diseasesand disorders are listed in U.S. Pat. No. 6,413,974 cited earlier,incorporated by reference herein.

More specifically, the compounds of Formula (I) can be useful in thetreatment of a variety of cancers, including (but not limited to) thefollowing: carcinoma, including that of the bladder, breast, colon,kidney, liver, lung, including small cell lung cancer, non-small celllung cancer, head and neck, esophagus, gall bladder, ovary, pancreas,stomach, cervix, thyroid, prostate, and skin, including squamous cellcarcinoma;

hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy celllymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma;

hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia;

tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma;

tumors of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma and schwannomas; and

other tumors, including melanoma, seminoma, teratocarcinoma,osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroidfollicular cancer and Kaposi's sarcoma.

Due to the key role of CDKs in the regulation of cellular proliferationin general, inhibitors could act as reversible cytostatic agents whichmay be useful in the treatment of any disease process which featuresabnormal cellular proliferation, e.g., benign prostate hyperplasia,familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosisfollowing angioplasty or vascular surgery, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, endotoxic shock,and fungal infections.

Compounds of Formula (I) may also be useful in the treatment ofAlzheimer's disease, as suggested by the recent finding that CDK5 isinvolved in the phosphorylation of tau protein (J. Biochem, (1995) 117,741-749).

Compounds of Formula (I) may induce or inhibit apoptosis. The apoptoticresponse is aberrant in a variety of human diseases. Compounds ofFormula I, as modulators of apoptosis, will be useful in the treatmentof cancer (including but not limited to those types mentionedhereinabove), viral infections (including but not limited to herpevirus,poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), preventionof AIDS development in HIV-infected individuals, autoimmune diseases(including but not limited to systemic lupus, erythematosus, autoimmunemediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, and autoimmune diabetes mellitus),neurodegenerative disorders (including but not limited to Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotrophic lateralsclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellardegeneration), myelodysplastic syndromes, aplastic anemia, ischemicinjury associated with myocardial infarctions, stroke and reperfusioninjury, arrhythmia, atherosclerosis, toxin-induced or alcohol relatedliver diseases, hematological diseases (including but not limited tochronic anemia and aplastic anemia), degenerative diseases of themusculoskeletal system (including but not limited to osteoporosis andarthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

Compounds of Formula (I), as inhibitors of the CDKs, can modulate thelevel of cellular RNA and DNA synthesis. These agents would therefore beuseful in the treatment of viral infections (including but not limitedto HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barrvirus, Sindbis virus and adenovirus).

Compounds of Formula (I) may also be useful in the chemoprevention ofcancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

Compounds of Formula (I) may also be useful in inhibiting tumorangiogenesis and metastasis.

Compounds of Formula (I) may also act as inhibitors of other proteinkinases, e.g., protein kinase C, her2, raf 1, MEK1, MAP kinase, EGFreceptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abland thus be effective in the treatment of diseases associated with otherprotein kinases.

Another aspect of this invention is a method of treating a mammal (e.g.,human) having a disease or condition associated with the CDKs byadministering a therapeutically effective amount of at least onecompound of Formula (I), or a pharmaceutically acceptable salt, solvate,ester, or prodrug of the compound to the mammal.

A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of thecompound of Formula (I). An especially preferred dosage is about 0.01 to25 mg/kg of body weight/day of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or prodrug of thecompound.

The compounds of this invention may also be useful in combination(administered together or sequentially) with one or more of anti-cancertreatments such as radiation therapy, and/or one or more anti-canceragents different from the compound of Formula (I). The compounds of thepresent invention can be present in the same dosage unit as theanti-cancer agent or in separate dosage units.

Another aspect of the present invention is a method of treating one ormore diseases associated with cyclin dependent kinase, comprisingadministering to a mammal in need of such treatment an amount of a firstcompound, which is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, ester, or prodrug thereof; and an amount of atleast one second compound, the second compound being an anti-canceragent different from the compound of Formula (I), wherein the amounts ofthe first compound and the second compound result in a therapeuticeffect.

Non-limiting examples of suitable anti-cancer agents include cytostaticagents, cytotoxic agents (such as for example, but not limited to, DNAinteractive agents (such as cisplatin or doxorubicin)); taxanes (e.g.taxotere, taxol); topoisomerase II inhibitors (such as etoposide);topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar,or topotecan); tubulin interacting agents (such as paclitaxel, docetaxelor the epothilones); hormonal agents (such as tamoxifen); thymidilatesynthase inhibitors (such as 5-fluorouracil); anti-metabolites (such asmethoxtrexate); alkylating agents (such as temozolomide (TEMODAR™ fromSchering-Plough Corporation, Kenilworth, N.J.), cyclophosphamide);Farnesyl protein transferase inhibitors (such as,SARASAR™(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoehtyl]-1-piperidinecarboxamide,or SCH 66336 from Schering-Plough Corporation, Kenilworth, N.J.),tipifarnib (Zarnestra® or R115777 from Janssen Pharmaceuticals),L778,123 (a farnesyl protein transferase inhibitor from Merck & Company,Whitehouse Station, N.J.), BMS 214662 (a farnesyl protein transferaseinhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.);signal transduction inhibitors (such as, Iressa (from Astra ZenecaPharmaceuticals, England), Tarceva (EGFR kinase inhibitors), antibodiesto EGFR (e.g., C225), GLEEVEC™ (C-abl kinase inhibitor from NovartisPharmaceuticals, East Hanover, N.J.); interferons such as, for example,intron (from Schering-Plough Corporation), Peg-Intron (fromSchering-Plough Corporation); hormonal therapy combinations; aromatasecombinations; ara-C, adriamycin, cytoxan, and gemcitabine.

Other anti-cancer (also known as anti-neoplastic) agents include but arenot limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin (ELOXATIN™ from Sanofi-Synthelabo Pharmaceuticals, France),Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Ifosfomide, Rituximab, C225, and Campath.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange. For example, the CDC2 inhibitor olomucine has been found to actsynergistically with known cytotoxic agents in inducing apoptosis (J.Cell Sci., (1995) 108, 2897. Compounds of Formula (I) may also beadministered sequentially with known anticancer or cytotoxic agents whena combination formulation is inappropriate. The invention is not limitedin the sequence of administration; compounds of Formula (I) may beadministered either prior to or after administration of the knownanticancer or cytotoxic agent. For example, the cytotoxic activity ofthe cyclin-dependent kinase inhibitor flavopiridol is affected by thesequence of administration with anticancer agents. Cancer Research,(1997) 57, 3375. Such techniques are within the skills of personsskilled in the art as well as attending physicians.

Accordingly, in an aspect, this invention includes combinationscomprising an amount of at least one compound of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or prodrug thereof,and an amount of one or more anti-cancer treatments and anti-canceragents listed above wherein the amounts of the compounds/treatmentsresult in desired therapeutic effect.

A method of inhibiting one or more Checkpoint kinases in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of at least one compound of Formula (I) or apharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

Another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or moreCheckpoint kinases in a patient in need thereof, comprisingadministering a therapeutically effective amount of at least onecompound of Formula (I) or a pharmaceutically acceptable salt, solvate,ester, or prodrug thereof.

Yet another aspect of the present invention is a method of treating oneor more diseases associated with Checkpoint kinases, comprisingadministering to a mammal in need of such treatment an amount of a firstcompound, which is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, ester, or prodrug thereof; and an amount of atleast one second compound, the second compound being an anti-canceragent, wherein the amounts of the first compound and the second compoundresult in a therapeutic effect.

Another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or moreCheckpoint kinases in a patient in need thereof, comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising in combination at least one pharmaceuticallyacceptable carrier and at least one compound according to Formula (I),or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof.

In the above methods, the checkpoint kinase to be inhibited can be Chk1and/or Chk2.

Another aspect of the present invention is a method of inhibiting one ormore tyrosine kinases in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of atleast one compound of Formula (I) or a pharmaceutically acceptable salt,solvate, ester, or prodrug thereof.

Yet another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or more of Aktkinases, Aurora kinase, and tyrosine kinases in a patient in needthereof, comprising administering a therapeutically effective amount ofat least one compound of Formula (I) or a pharmaceutically acceptablesalt, solvate, ester, or prodrug thereof.

Another aspect of the present invention is a method of treating one ormore diseases associated with Akt kinases, Aurora kinases and/ortyrosine kinases, comprising administering to a mammal in need of suchtreatment an amount of a first compound, which is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof; and an amount of at least one second compound, the secondcompound being an anti-cancer agent, wherein the amounts of the firstcompound and the second compound result in a therapeutic effect.

Another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or more of Aktkinases, Aurora kinases and tyrosine kinases in a patient in needthereof, comprising administering a therapeutically effective amount ofa pharmaceutical composition comprising in combination at least onepharmaceutically acceptable carrier and at least one compound of Formula(I) or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof.

In the above methods, the tyrosine kinase can be VEGFR, EGFR, HER2, SRC,JAK and/or TEK.

Yet another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with Pim-1 kinases in apatient in need thereof, comprising administering a therapeuticallyeffective amount of at least one compound of Formula (I) or apharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

Another aspect of the present invention is a method of treating one ormore diseases associated with Pim-1 kinases, comprising administering toa mammal in need of such treatment an amount of a first compound, whichis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, ester, or prodrug thereof; and an amount of at least one secondcompound, the second compound being an anti-cancer agent, wherein theamounts of the first compound and the second compound result in atherapeutic effect.

Another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with Pim-1 kinases in apatient in need thereof, comprising administering a therapeuticallyeffective amount of a pharmaceutical composition comprising incombination at least one pharmaceutically acceptable carrier and atleast one compound of Formula (I) or a pharmaceutically acceptable salt,solvate, ester, or prodrug thereof.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which are described herein below have beencarried out with compounds according to the invention and their salts.

This invention is also directed to pharmaceutical compositions whichcomprise at least one compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, ester, or prodrug of the compound and at leastone pharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally or intravenously.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or prodrug of thecompound and a pharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, ester, or prodrug of the compound and an amount of atleast one anticancer therapy and/or anti-cancer agent listed above,wherein the amounts of the two or more ingredients result in desiredtherapeutic effect.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

Where NMR data are presented, ¹H spectra were obtained on either aVarian VXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHz) or XL-400 (400MHz) and are reported as ppm down field from Me₄Si with number ofprotons, multiplicities, and coupling constants in Hertz indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing an Applied Biosystems API-100 mass spectrometer and ShimadzuSCL-10A LC column: Altech platinum C18, 3 micron, 33 mm×7 mm ID;gradient flow: 0 min—10% CH₃CN, 5 min—95% CH₃CN, 7 min—95% CH₃CN, 7.5min—10% CH₃CN, 9 min—stop. The retention time and observed parent ionare given.

The following solvents and reagents may be referred to by theirabbreviations in parenthesis:

-   Thin layer chromatography: TLC-   dichloromethane: CH₂Cl₂-   ethyl acetate: AcOEt or EtOAc-   methanol: MeOH-   trifluoroacetate: TFA-   triethylamine: Et₃N or TEA-   butoxycarbonyl: n-Boc or Boc-   nuclear magnetic resonance spectroscopy: NMR-   liquid chromatography mass spectrometry: LCMS-   high resolution mass spectrometry: HRMS-   milliliters: mL-   millimoles: mmol-   microliters: μl-   grams: g-   milligrams: mg-   room temperature or rt (ambient): about 25° C.-   dimethoxyethane: DME

In general, the compounds described in this invention can be preparedthrough the general routes described below in the Scheme 1 shown below.

PREPARATIVE EXAMPLES AND EXAMPLES Preparative Examples PreparativeExample 1

To a stirred suspension of diethyl malonimidate dichloride (23.1 g, 0.10mol) in Et₂O was added at 0° C. aqueous saturated solution of K₂CO₃ (200mL). The mixture was stirred under N₂ at 0° C. for 5 min, then separatedin a separatory funnel, and the aqueous part was extracted with Et₂O(2×200 mL). The combined ether extracts were dried over Na₂SO₄,filtered, and the solvent was evaporated. The resulting colorless oil(14.9 g) was added in portions to a stirred boiling solution of 99%N₂H₄.H₂O (4.71 g, 94.3 mmol) in EtOH (45 mL), the mixture was stirredfor 10 min and then kept at 4° C. for 16 hr. The solvent was evaporatedand the residue was purified by column chromatography on silicagel with4:1 CH₂Cl₂/7N NH₃ in MeOH as eluent. Pale yellow solid (4.40 g, 48%) wasobtained.

Preparative Example 2

A mixture of the product from Preparative Example 1 (980 mg, 10.0 mmol)and ethyl benzoylacetate (2.20 g, 11.5 mmol) in AcOH (15 mL) was stirredand refluxed under N₂ for 5 hr. The mixture was cooled to 25° C., thesolid was filtered off, washed on filter with AcOH (20 mL), Et₂O (40mL), and dried in a vacuum. Cream-colored solid (930, 35%) was obtained.Mp>300° C. LC-MS: 269 [M+H].

Preparative Example 3

By essentially same procedure set forth in Preparative Example 2,compound given below was prepared from ethyl acetoacetate and compoundfrom Preparative Example 1.

Mp>300° C. LC-MS: 207 [M+H].

Preparative Example 4

A mixture of the product from Preparative Example 2 (440 mg, 1.64 mmol),N,N-dimethylaniline (0.63 mL), and POCl₃ (5.0 mL) was stirred under N₂at 25° C. for 4 d. The solvent was evaporated and the residue waspurified by column chromatography on silicagel with 2:1 CH₂Cl₂/EtOAc aseluent. Pale yellow solid (225 mg, 48%) was obtained. LC-MS: 287 [M+].

Preparative Example 5

By essentially same procedure set forth in Preparative Example 4,compound given below was prepared.

LC-MS: 225 [M+].

Preparative Example 6

A solution of NBS (62 mg, 0.35 mmol) in anhydrous CH₃CN (3 mL) was addedunder N₂ to a stirred solution of the product from Preparative Example 4(100 mg, 0.35 mmol) in anhydrous CH₃CN (3 mL) and CH₂Cl₂ (6 mL). Themixture was stirred for 2 hr, the solvents were evaporated, and theresidue was purified by column chromatography on silicagel with 3:2CH₂Cl₂/EtOAc as eluent. Pale yellow solid (52 mg, 41%) was obtained.LC-MS: 367 [M+H].

Preparative Example 7

A mixture of the product from Preparative Example 4 (50 mg, 0.17 mmol),2.0 M NH₃ in 2-propanol (2.0 mL), and conc. aqueous NH₄OH (0.2 mL) wasstirred in a closed pressure vessel at 60° C. for 20 hr. The solventswere evaporated and the residue was purified by column chromatography onsilicagel with 8:1 CH₂Cl₂/MeOH as eluent. Pale yellow solid (30 mg, 64%)was obtained.

Mp=258-260° C. LC-MS: 268 [M+H].

Preparative Example 8

By essentially same procedure set forth in Preparative Example 7,compound given below was prepared.

Mp=90-92° C. LC-MS: 346 [M+].

Preparative Example 9

A mixture of the product from Preparative Example 2 (100 mg, 0.37 mmol)and KOH (200 mg), in EtOH (5 mL) and H₂O (1 mL) was stirred and refluxedunder N₂ for 8 h. The solvent was evaporated and the residue waspurified by column chromatography on silicagel with 5:1 CH₂Cl₂/MeOH aseluent. Pale yellow solid (6 mg, 7%) was obtained. Mp=175-177° C. LC-MS:227 [M+H].

Preparative Example 10-11

By essentially same procedure set forth in Preparative Example 9,compounds given below were prepared.

Mp=207-209° C. LC-MS: 227 [M+2H].

Mp=211-213° C. LC-MS: 306 [M+2H].

Preparative Example 12

A mixture of the product from Preparative Example 5 (224 mg, 1.00 mmol)and sodium thiomethoxide (77 mg, 1.10 mmol) in THF (5 mL) was stirred at25° C. under N₂ for 20 h. The solvent was evaporated and the residue waspurified by column chromatography on silicagel with 10:1 CH₂Cl₂/MeOH aseluent. White solid (210 mg, 89%) was obtained. LC-MS: 237 [M+H].

EXAMPLES Example 1

A mixture of the product from Preparative Example 2 (100 mg, 0.37 mmol)and KOH (200 mg), in EtOH (5 mL) and H₂O (1 mL) was stirred and refluxedunder N₂ for 8 h. The solvent was evaporated and the residue waspurified by column chromatography on silicagel with 5:1 CH₂Cl₂/MeOH aseluent. Pale yellow solid (6 mg, 7%) was obtained. Mp=175-177° C. LC-MS:227 [M+H].

Example 2

By essentially the same procedure set forth in Example 1, the compoundgiven below was prepared.

Mp=207-209° C. LC-MS: 227 [M+2H].

Example 3

By essentially the same procedure set forth in Example 1, the compoundgiven below was prepared.

Mp=211-213° C. LC-MS: 306 [M+2H].

Assays:

CHK1 SPA Assay

An in vitro assay has been developed that utilizes recombinant His-CHK1expressed in the baculovirus expression system as an enzyme source and abiotinylated peptide based on CDC25C as substrate(biotin-RSGLYRSPSMPENLNRPR).

Materials and Reagents:

-   1) CDC25C Ser 216 C-term Biotinylated peptide substrate (25 mg),    stored at −20° C., Custom Synthesis by Research Genetics:    biotin-RSGLYRSPSMPENLNRPR 2595.4 MW-   2) His-CHK1 In House lot P976, 235 ug/mL, stored at −80° C.-   3) D-PBS (without CaCl and MgCl): GIBCO, Cat.# 14190-144-   4) SPA beads: Amersham, Cat.# SPQ0032: 500 mg/vial

Add 10 mls of D-PBS to 500 mg of SPA beads to make a workingconcentration of 50 mg/ml. Store at 4° C. Use within 2 week afterhydration.

-   5) 96-Well White Microplate with Bonded GF/B filter: Packard, Cat.#    6005177-   6) Top seal-A 96 well Adhesive Film: Perkin Elmer, Cat.# 6005185-   7) 96-well Non-Binding White Polystyrene Plate: Corning, Cat. #    6005177-   8) MgCl₂: Sigma, Cat.# M-8266-   9) DTT: Promega, Cat.# V3155-   10) ATP, stored at 4° C.: Sigma, Cat.# A-5394-   11) γ³³P-ATP, 1000-3000 Ci/mMol: Amersham, Cat.# AH9968-   12) NaCl: Fisher Scientific, Cat.# BP358-212-   13) H₃PO₄ 85% Fisher, Cat.#A242-500-   14) Tris-HCL pH 8.0: Bio-Whittaker, Cat. # 16-015V-   15) Staurosporine, 100 ug: CALBIOCHEM, Cat. # 569397-   16) Hypure Cell Culture Grade Water, 500 mL: HyClone, Cat.#    SH30529.02    Reaction Mixtures:-   1) Kinase Buffer: 50 mM Tris pH 8.0; 10 mM MgCl₂; 1 mM DTT-   2) His-CHK1, In House Lot P976, MW ˜30 KDa, stored at −80° C.

6 nM is required to yield positive controls of ˜5,000 CPM. For 1 plate(100 r×n): dilute 8 uL of 235 ug/mL (7.83 uM) stock in 2 mL KinaseBuffer. This makes a 31 nM mixture. Add 20 uL/well. This makes a finalreaction concentration of 6 nM.

-   3) CDC25C Biotinylated peptide.

Dilute CDC25C to 1 mg/mL (385 uM) stock and store at −20° C. For 1 plate(100 r×n): dilute 10 uL of 1 mg/mL peptide stock in 2 ml Kinase Buffer.This gives a 1.925 uM mix. Add 20 uL/rxn. This makes a final reactionconcentration of 385 nM.

-   4) ATP Mix.

For 1 plate (100 r×n): dilute 10 uL of 1 mM ATP (cold) stock and 2 uLfresh P33-ATP (20 uCi) in 5 ml Kinase Buffer. This gives a 2 uM ATP(cold) solution; add 50 ul/well to start the reaction. Final volume is100 ul/rxn so the final reaction concentrations will be 1 uM ATP (cold)and 0.2 uCi/rxn.

-   5) Stop Solution:

For 1 plate add: To 10 mL Wash Buffer 2 (2M NaCl 1% H₃PO₄): 1 mL SPAbead slurry (50 mg); Add 100 uL/well

-   6) Wash buffer 1: 2 M NaCl-   7) Wash buffer 2: 2 M NaCl, 1% H₃PO₄    Assay Procedure:

Assay Final Component Concentration Volume CHK1 6 nM 20 μl/rxn Compound— 10 μl/rxn (10% DMSO) CDC25C 0.385 μM 20 μl/rxn γ³³P-ATP 0.2 μCi/rxn 50μl/rxn Cold ATP 1 μM Stop solution 0.5 mg/rxn 100 μl/rxn* SPA beads  200μl/rxn** *Total reaction volume for assay. **Final reaction volume attermination of reaction (after addition of stop solution).

-   1) Dilute compounds to desired concentrations in water/10% DMSO—this    will give a final DMSO concentration of 1% in the r×n. Dispense 10    □l/rxn to appropriate wells. Add 10 uL 10% DMSO to positive    (CHK1+CDC25C+ATP) and negative (CHK1+ATP only) control wells.-   2) Thaw enzyme on ice—dilute enzyme to proper concentration in    kinase buffer (see Reaction Mixtures) and dispense 20 □l to each    well.-   3) Thaw the Biotinylated substrate on ice and dilute in kinase    buffer (see Reaction Mixtures). Add 20 uL/well except to negative    control wells. Instead, add 20 uL Kinase Buffer to these wells.-   4) Dilute ATP (cold) and P33-ATP in kinase buffer (see Reaction    Mixtures). Add 50 uL/well to start the reaction.-   5) Allow the reaction to run for 2 hours at room temperature.-   6) Stop reaction by adding 100 uL of the SPA beads/stop solution    (see Reaction Mixtures) and leave to incubate for 15 minutes before    harvest-   7) Place a blank Packard GF/B filter plate into the vacuum filter    device (Packard plate harvester) and aspirate 200 mL water through    to wet the system.-   8) Take out the blank and put in the Packard GF/B filter plate.-   9) Aspirate the reaction through the filter plate.-   10) Wash: 200 ml each wash; 1× with 2M NaCl; 1× with 2M NaCl/1%    H₃PO₄-   11) Allow filter plate to dry 15 min.-   12) Put TopSeal-A adhesive on top of filter plate.-   13) Run filter plate in Top Count

Settings: Data mode: CPM

-   -   Radio nuclide: Manual SPA:P33    -   Scintillator: Liq/plast    -   Energy Range: Low        CDK2 Assay:        BACULOVIRUS CONSTRUCTIONS: Cyclins A and E were cloned into        pFASTBAC (Invitrogen) by PCR, with the addition of a GluTAG        sequence (EYMPME) at the amino-terminal end to allow        purification on anti-GluTAG affinity columns. The expressed        proteins were approximately 46 kDa (cyclin E) and 50 kDa        (cyclin A) in size. CDK2 was also cloned into pFASTBAC by PCR,        with the addition of a haemaglutinin epitope tag at the        carboxy-terminal end (YDVPDYAS). The expressed protein was        approximately 34 kDa in size.        ENZYME PRODUCTION: Recombinant baculoviruses expressing cyclins        A, E and CDK2 were infected into SF9 cells at a multiplicity of        infection (MOI) of 5, for 48 hrs. Cells were harvested by        centrifugation at 1000 RPM for 10 minutes. Cyclin-containing (E        or A) pellets were combined with CDK2 containing cell pellets        and lysed on ice for 30 minutes in five times the pellet volume        of lysis buffer containing 50 mM Tris pH 8.0, 0.5% NP40, 1 mM        DTT and protease/phosphatase inhibitors (Roche Diagnostics GmbH,        Mannheim, Germany). Mixtures were stirred for 30-60 minutes to        promote cyclin-CDK2 complex formation. Mixed lysates were then        spun down at 15000 RPM for 10 minutes and the supernatant        retained. 5 ml of anti-GluTAG beads (for one liter of SF9 cells)        were then used to capture cyclin-CDK2 complexes. Bound beads        were washed three times in lysis buffer. Proteins were        competitively eluted with lysis buffer containing 100-200 ug/mL        of the GluTAG peptide. Eluate was dialyzed overnight in 2 liters        of kinase buffer containing 50 mM Tris pH 8.0, 1 mM DTT, 10 mM        MgCl2, 100 uM sodium orthovanadate and 20% glycerol. Enzyme was        stored in aliquots at −70° C.        IN VITRO KINASE ASSAY: CDK2 kinase assays (either cyclin A or        E-dependent) were performed in low protein binding 96-well        plates (Corning Inc, Corning, N.Y.). Enzyme was diluted to a        final concentration of 50 μg/ml in kinase buffer containing 50        mM Tris pH 8.0, 10 mM MgCl₂,1 mM DTT, and 0.1 mM sodium        orthovanadate. The substrate used in these reactions was a        biotinylated peptide derived from Histone H1 (from Amersham,        UK). The substrate was thawed on ice and diluted to 2 μM in        kinase buffer. Compounds were diluted in 10% DMSO to desirable        concentrations. For each kinase reaction, 20 μl of the 50 μg/ml        enzyme solution (1 μg of enzyme) and 20 μl of the 1 μM substrate        solution were mixed, then combined with 10 μl of diluted        compound in each well for testing. The kinase reaction was        started by addition of 50 μl of 4 μM ATP and 1 μCi of 33P-ATP        (from Amersham, UK). The reaction was allowed to run for 1 hour        at room temperature. The reaction was stopped by adding 200 μl        of stop buffer containing 0.1% Triton X-100, 1 mM ATP, 5 mM        EDTA, and 5 mg/ml streptavidine coated SPA beads (from Amersham,        UK) for 15 minutes. The SPA beads were then captured onto a        96-well GF/B filter plate (Packard/Perkin Elmer Life Sciences)        using a Filtermate universal harvester (Packard/Perkin Elmer        Life Sciences.). Non-specific signals were eliminated by washing        the beads twice with 2M NaCl then twice with 2 M NaCl with 1%        phosphoric acid. The radioactive signal was then measured using        a TopCount 96 well liquid scintillation counter (from        Packard/Perkin Elmer Life Sciences).        IC₅₀ DETERMINATION: Dose-response curves were plotted from        inhibition data generated, each in duplicate, from 8 point        serial dilutions of inhibitory compounds. Concentration of        compound was plotted against % kinase activity, calculated by        CPM of treated samples divided by CPM of untreated samples. To        generate IC₅₀ values, the dose-response curves were then fitted        to a standard sigmoidal curve and IC₅₀ values were derived by        nonlinear regression analysis. The thus-obtained IC₅₀ values for        selected compounds of the invention are shown in Table 1 above.        These kinase activities were generated by using the        above-described assay.

As demonstrated above by the assay values, the compounds of the presentinvention can exhibit good Chk1 inhibitory properties.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound represented by the structural formula (I):

or a pharmaceutically acceptable salt of the compound of formula (I),wherein: R² is selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, alkenylalkyl,alkynylalkyl, heterocyclyl, heterocycloalkyl, trifluoromethyl, halo,—OCF₃, —CO₂R⁸, —CONR⁸R⁹, —OR^(8a), —SR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂R⁹,—NR⁸COR⁹, and —NR⁸CONR⁸R⁹; R³ is selected from the group consisting ofhaloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —NR⁵R^(8a), —NR⁸COR⁹,—NR⁸SO₂R⁹, —COR⁸, —CO₂R⁸, —CONR⁸R⁹, —CH₂OR⁸, —OR^(8b), —SR⁸, —SO₂R⁸,—S(O₂)NR⁸R⁹, —S(O₂)aryl, —S(O₂)heteroaryl, —C(O)NR⁸R⁹, —C(O)OR⁹,—C(O)aryl, —C(O)heteroaryl, —(CHR⁵)_(n)-aryl, —(CHR⁵)_(n)-heteroaryl,

wherein each of the alkyl, alkenyl, alkynyl, aryl, arylalkyl,arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and theheterocyclic moieties shown immediately above for R³ can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of H, halo, alkyl, trifluoromethyl, —OR⁸,—NR⁸R⁹, —SR⁸, —SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and —NO₂.; R⁴ is selectedfrom the group consisting of H, halo, haloalkyl, alkyl, alkenyl,alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl,alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —NR⁸R⁹, —NR⁸COR⁹, —NR⁸SO₂R⁹, —COR⁸, —CO₂R⁸, —CONR⁸R⁹,—CH₂OR⁸, —OR⁸, —SR⁸, —SO₂R⁸, —S(O₂)NR⁸R⁹, —S(O₂)aryl, —S(O₂)heteroaryl,—C(O)OR⁹, —C(O)aryl, —C(O)heteroaryl, —(CHR⁵)_(n)-aryl,—(CHR⁵)_(n)-heteroaryl,

wherein each of the alkyl, alkenyl, alkynyl, aryl, arylalkyl,arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and theheterocyclic moieties shown immediately above for R⁴ can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of H, halo, alkyl, trifluoromethyl, —OR⁸,—NR⁸R⁹, —SR⁸, —SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and —NO₂; R^(a) is selectedfrom the group consisting of H, halo, haloalkyl, alkyl, alkenyl,alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl,alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —NR⁸R⁹, —NR⁸COR⁹, —NR⁸SO₂R⁹, —COR⁸, —CO₂R⁸, —CONR⁸R⁹,—CH₂OR⁸, —OR⁸, —SR⁸, —SO₂R⁸, —S(O₂)NR⁸R⁹, —S(O₂)aryl, —S(O₂)heteroaryl,—C(O)OR⁹, —C(O)aryl, —C(O)heteroaryl, —(CHR⁵)_(n)-aryl,—(CHR⁵)_(n)-heteroaryl,

wherein each of the alkyl, alkenyl, alkynyl, aryl, arylalkyl,arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl alkyl and theheterocyclic moieties shown immediately above for R^(a) can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of H, halo, alkyl, trifluoromethyl, —OR⁸,—NR⁸R⁹, —SR⁸, —SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and —NO₂; R⁵ is selectedfrom the group consisting of H, alkyl, aryl or cycloalkyl; R⁶ isselected from the group consisting of H, alkyl, alkenyl, aryl,arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl,aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, and heteroarylalkyl groups can be unsubstituted oroptionally substituted with one or more moieties which can be the sameor different, each moiety being independently selected from the groupconsisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF₃,—OCF₃, —CN, —OR⁵, —NR⁵R¹⁰, —(CR⁵R¹¹)_(p)—R⁹, —N(R⁵)(Butoxycarbonyl),—(CR⁵R¹¹)_(p)OR⁵, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰,—S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰; R⁷ is selected from the group consisting of alkyl,cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl,heteroarylalkenyl, and heterocyclyl, wherein each of the alkyl,cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl,heteroarylalkyl, heteroarylalkenyl, and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —CH₂OR⁵, —C(O₂)R⁵,—C(O)NR⁵R¹⁰, —C(O)R⁵, —SR¹⁰, —S(O₂)R¹⁰, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R¹⁰,—N(R⁵)C(O)R¹⁰ and —N(R⁵)C(O)NR⁵R¹⁰; R⁸ is selected from the groupconsisting of H, —OR⁶, —NR⁵R⁶, —C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷,—C(═N—CN)—NH₂, —C(═NH)—NHR⁵, heterocyclyl, —S(O₂)R⁷,

—OR¹⁰, —CF₃, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl,wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groupscan be unsubstituted or optionally substituted with one or more moietieswhich can be the same or different, each moiety being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,heterocyclylalkyl, —CF₃, —OCF₃, —CN, —OR⁵, —NR⁵R¹⁰, —(CR⁵R¹¹)_(p)—R⁹,—N(R⁵)(Butoxcarbonyl), —(CR⁵R¹¹)_(p)OR⁵, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰,—SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰; R^(8a) is selected from the group consisting of —OR⁶,—NR⁵R⁶, —C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷, —C(═N—CN)—NH₂, —C(═NH)—NHR⁵,heterocyclyl, —S(O₂)R⁷,

—OR¹⁰, —CF₃, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl,wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groupscan be unsubstituted or optionally substituted with one or more moietieswhich can be the same or different, each moiety being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,heterocyclylalkyl, —CF₃, —OCF₃, —CN, —OR⁵, —NR⁵R¹⁰, —(CR⁵R¹¹)_(p)—R⁹,—N(R⁵)Butoxycarbonyl), —(CR⁵R¹¹)_(p)OR⁵, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰,—SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰; R^(8b) is selected from the group consisting of —OR⁶,—NR⁵R⁶, —C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷, —C(═N—CN)—NH₂, —C(═NH)—NHR⁵,heterocyclyl, —S(O₂)R⁷,

—OR¹⁰, —CF₃, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl,wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of halo, alkyl, aryl, cycloalkyl,heterocyclylalkyl, —CF₃, —OCF₃, —CN, —OR⁵, —NR⁵R¹⁰, —(CR⁵R¹¹)_(p)—R⁹,—N(R⁵)(Butoxycarbonyl), —(CR⁵R¹¹)_(p)OR⁵, —C(O₂)R⁵, —C(O)R⁵,—C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰; R⁹ is selected from the groupconsisting of H, —OR⁶, —NR⁵R⁶, —C(O)NR⁵R¹⁰, —S(O₂)NR⁵R¹⁰, —C(O)R⁷,—C(═N—CN)—NH₂, —C(═NH)—NHR⁵, heterocyclyl, —S(O₂)R⁷,

—OR¹⁰, —CF₃, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl,wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groupscan be unsubstituted or optionally substituted with one or more moietieswhich can be the same or different, each moiety being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,heterocyclylalkyl, —CF₃, —OCF₃, —CN —OR⁵, —NR⁵R¹⁰,—N(R⁵)(Butoxycarbonyl), —(CR⁵R¹¹)_(p)OR⁵, —C(O₂)R⁵, —C(O)R⁵,—C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰; R¹⁰ is selected from the groupconsisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroarylalkyl groups can be unsubstituted or optionally substitutedwith one or more moieties which can be the same or different, eachmoiety being independently selected from the group consisting of halo,alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF₃, —OCF₃, —CN, —OR⁵,—NR⁵R¹¹, —(CR⁵R¹¹)_(p)—R⁹, —N(R⁵)Butoxcarbonyl, —(CR⁵R¹¹)_(p)OR⁵,—C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹, —SO₃H, —SR¹¹, —S(O₂)R⁷, —S(O₂)NR⁵R¹¹,—N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹¹; or optionally (i) R⁵and R¹¹ in the moiety —NR⁵R¹¹, or (ii) R⁵ and R⁶ in the moiety —NR⁵R⁶,may be joined together to form a heterocyclyl moiety, with theheterocyclyl moiety being unsubstituted or optionally independentlybeing substituted with one or more R⁹ groups; and R¹¹ is H, halo oralkyl; m is 0 to 4; n is 1 to 4; and p is 1 to 4; with the followingprovisos: (a) when R⁴and R^(a), are selected from the group consistingof —NH₂, —OH, alkynyl, alkenylalkyl, and alkynylalkyl, then R² isselected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, alkenylalkyl,alkynylalkyl, trifluoromethyl, —OCF₃, —OR^(8a), —SR⁸, and —NR⁸CONR⁸R⁹.2. The compound according to claim 1, wherein R² is H.
 3. The compoundaccording to claim 1, wherein R² is Br.
 4. The compound according toclaim 1, wherein R² is selected from the group consisting of Cl, —SH,—CN, alkyl, alkenyl, alkynyl, and cyclopropyl.
 5. The compound accordingto claim 1, wherein R² is selected from the group consisting ofcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, —OCF₃,—CO₂R⁸, —CONR⁸R⁹, —OR^(8a), —SR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂R⁹,—NR⁸COR⁹, and —NR⁸CONR⁸R⁹.
 6. The compound according to claim 1, whereinR³ is benzyl.
 7. The compound according to claim 1, wherein R³ isselected from the group consisting of aryl, arylalkyl, arylalkenyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —S(O₂)aryl, —S(O₂)heteroaryl, —C(O)aryl,—C(O)heteroaryl, —(CHR⁵)_(n)-aryl, —(CHR⁵)_(n)-heteroaryl,

wherein each of the aryl, arylalkyl, arylalkenyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl and the heterocyclic moieties shown immediately abovefor R³ can be unsubstituted or optionally substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from the group consisting of H, halo, alkyl,trifluoromethyl, —OR⁸, —NR⁸R⁹, —SR⁸, —SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and—NO_(2.)
 8. The compound according to claim 1, wherein R³ is selectedfrom the group consisting of haloalkyl, alkenyl, alkynyl, alkenylalkyl,alkynylalkyl, —NR⁵R^(8a), —NR⁸COR⁹, —NR⁸SO₂R⁹, —COR⁸, —CO₂R⁸, —CONR⁸R⁹,—CH₂OR⁸, —OR^(8b), —SR⁸, —SO₂R⁸, —S(O₂)NR⁸R⁹, wherein each of thealkenyl, alkynyl, alkenylalkyl, alkynylalkyl, can be unsubstituted oroptionally substituted with one or more moieties which can be the sameor different, each moiety being independently selected from the groupconsisting of H, halo, alkyl, trifluoromethyl, —OR⁸, —NR⁸R⁹, —SR⁸,—SO₂R⁹, —CN, —SO₂NR⁸R⁹, —CF₃, and —NO₂.
 9. The compound according toclaim 1, wherein R³ is OR^(8b).
 10. The compound according to claim 1,wherein R³ is alkylthio.
 11. The compound according to claim 1, whereinR³ is selected from the group consisting of


12. The compound according to claim 1, wherein R³ is selected from thegroup consisting of heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl.
 13. The compound according to claim 1, wherein R⁴ isH.
 14. The compound according to claim 1, wherein R⁴ is selected fromthe group consisting of Cl, Br, —OH, —SH, alkyl, alkenyl, alkynyl,haloalkyl and cyclopropyl.
 15. The compound according to claim 1,wherein R⁴ is —NH₂.
 16. The compound according to claim 1, wherein R⁴ is—OH.
 17. The compound according to claim 1, wherein R⁴ is alkoxy. 18.The compound according to claim 1, wherein R⁴ is alkylthio.
 19. Thecompound according to claim 1, wherein R⁴ is halo.
 20. The compoundaccording to claim 1, wherein R^(a) is —NH₂.
 21. The compound accordingto claim 1, wherein R^(a) is —OH.
 22. The compound according to claim 1,wherein R^(a) is alkoxy.
 23. The compound according to claim 1, whereinR^(a) is alkylthio.
 24. The compound according to claim 1, wherein R^(a)is halo.
 25. The compound according to claim 1, wherein R^(a) is Cl. 26.The compound according to claim 1, wherein R⁵ is H.
 27. The compoundaccording to claim 1, wherein n is
 1. 28. The compound according toclaim 1, wherein p is
 1. 29. The compound according to claim 1, whereinthe compound is selected from the group consisting of:


30. A compound according to claim 1 or a pharmaceutically acceptablesalt thereof in purified and isolated form.
 31. A pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound of claim 1 or a pharmaceutically acceptable salt thereof,in combination with at least one pharmaceutically acceptable carrier.